Elastin-derived extracellular matrix fragments drive aging through innate immune activation
The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals.
Authors
- Tianning Ye
- Jingyi Qian (ORCID: https://orcid.org/0000-0002-8793-9330)
- Yi-Shan Chen
- Xudong Yao (ORCID: https://orcid.org/0000-0001-6207-8514)
- Xiaohui Zou (ORCID: https://orcid.org/0000-0001-9563-0301)
- Junzhi Yi (ORCID: https://orcid.org/0000-0001-5636-1540)
- Zhichu Chen (ORCID: https://orcid.org/0000-0003-1907-4870)
- Xuri Chen (ORCID: https://orcid.org/0009-0008-7761-9000)
- Fangyuan Bao
- Zi Yin (ORCID: https://orcid.org/0000-0003-2892-8962)
- Jin Pan (ORCID: https://orcid.org/0000-0001-7218-9496)
- Hua Liu (ORCID: https://orcid.org/0000-0001-7729-1246)
- Yixuan Wang (ORCID: https://orcid.org/0000-0002-2518-0699)
- Tian Tian (ORCID: https://orcid.org/0000-0002-9225-1784)
- Xiao Xiao (ORCID: https://orcid.org/0000-0002-8687-5689)
- Yuliang Zhong
- Jing Zhou (ORCID: https://orcid.org/0000-0002-4969-9401)
- Jiasheng Wang (ORCID: https://orcid.org/0000-0003-3053-5439)
- Weiliang Shen (ORCID: https://orcid.org/0000-0001-8131-325X)
- Hongwei Ouyang (ORCID: https://orcid.org/0000-0003-0627-2536)
- Hui Zhang (ORCID: https://orcid.org/0009-0000-4393-2447)
- Jiayun Huang
- Bingbing Wu (ORCID: https://orcid.org/0000-0002-0250-104X)
- Yujuan Xie (ORCID: https://orcid.org/0000-0003-2116-7160)
- Xiaoping Xia (ORCID: https://orcid.org/0000-0003-3986-1214)
- Jiajie Hu
- Hairu Sui
Institutions
- Zhejiang International Studies University (CN)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Regenerative Medicine Institute (MX)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s43587-025-00961-8
- Citations
- 6
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 5.72